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Olanzapine for the Treatment of Psychosis in Patients With Parkinson's Disease and Dementia

Received February 27, 2001; revised June 28, 2001; accepted July 19, 2001. From the Morris K. Udall Parkinson's Disease Research Center of Excellence at Johns Hopkins, the Neuropsychiatry Service, Department of Psychiatry and Behavioral Sciences, and the Movement Disorders Center, Department of Neurology, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD. Address correspondence and reprint requests to Dr. Marsh, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St. Baltimore, MD 21287.

ABSTRACT

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Psychotic symptoms are a common complication in Parkinson's disease with dementia. The authors conducted an open-label 6-week trial of olanzapine preceded by a placebo lead-in in five subjects with Parkinson's disease, mild to moderately severe dementia, and psychosis. Four of the subjects terminated the trial early because of worsening motor function, sedation, or paranoia. There was no improvement in psychotic symptoms, and functional abilities declined significantly. Olanzapine appears to be poorly tolerated in patients with Parkinson's disease, psychotic symptoms, and dementia.

Key Words: Dementia • Psychosis • Parkinson's Disease

INTRODUCTION

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Psychosis develops in up to 40% of patients with Parkinson's disease (PD) and is the most common cause of nursing home placement.¹ Although antiparkinsonian therapies are often implicated, advanced disease and cognitive impairment are additional specific risks for psychosis² Trials of antipsychotics in those with PD typically focus on drug-induced psychosis and exclude patients with dementia, whose response to antipsychotic medications may differ from PD patients without dementia. Because PD patients with dementia and psychosis are a significant source of morbidity, caregiver burden, and complex management issues,³ treatment guidelines are needed.

This study examined the efficacy and safety of olanzapine for the treatment of psychosis in PD patients with dementia. Olanzapine is an atypical neuroleptic with a low affinity for striatal D₂ receptors and a reduced propensity for causing extrapyramidal symptoms.⁴ Its clinical qualities are similar to clozapine, an atypical neuroleptic that is generally effective and tolerated for psychosis in patients with PD.⁵ However, olanzapine does not have hematological side effects that require weekly blood monitoring.

METHOD

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Subjects
Subjects were recruited from the Johns Hopkins Movement Disorders Clinic and had idiopathic PD based on the United Kingdom Brain Bank Criteria,⁶ dementia secondary to PD based on DSM-IV criteria,⁷ and hallucinations and/or delusions for at least 4 weeks before study entry that were not accounted for by another medical or psychiatric cause. Subjects were recruited only after their antiparkinsonian medications were reduced to the lowest dose tolerated with respect to motor function. All participants or their caregivers provided informed consent.

Trial Procedures
Assessments were conducted at screening; baseline; and Weeks 1, 2, 4, and 6. Antiparkinsonian medications were stable for at least 7 days before patient screening, which included a physical examination, electrocardiogram, urinalysis, complete blood count, and a comprehensive chemistry panel. After a 4-to 8-day single-blind placebo lead-in, subjects who maintained a score >2 on the Schedule for the Assessment of Positive Symptoms (SAPS) Hallucinations or Delusions subscale⁸ were started on olanzapine (2.5 mg qhs). If treatment response plateaued and the patient was tolerating olanzapine, the dose was increased in 2.5-mg increments every 3 days (up to 15.0 mg qhs). Dose reductions occurred whenever side effects were intolerable.

Efficacy was measured as the change in psychosis severity using the SAPS score. Secondary efficacy measures included the Brief Psychiatric Rating Scale, Neuropsychiatric Inventory symptom severity and caregiver distress scores,⁹ and hours of sleep between 2100 and 0900. The primary safety measure was the Unified Parkinson's Disease Rating Scale (UPDRS) motor score.¹⁰ Additional safety assessments included orthostatic blood pressure and functional and cognitive abilities based on the UPDRS Activities of Daily Living Scale and Mini-Mental State Exam.¹¹

Statistical Analysis
With SPSS software, we used Wilcoxon's signed rank tests to test the change in rating scales from baseline to final assessment (last observation carried forward). The small sample size limits interpretation of these analyses.

RESULTS

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Medication Dosage and Study Completion
Five patients (2 women, 3 men) with mild to moderately severe dementia met enrollment criteria and received olanzapine (Table 1). No patient tolerated olanzapine at a dose greater than 2.5 mg because of worsened parkinsonism, though the maximum dose prescribed was 7.5 mg for one night. Subject 2 requested termination on Day 14 because of delusional ideation about the investigators that developed after he took tramadol. Subject 3 was withdrawn on Day 15 because of worsening motor function and psychosis. Subject 4 was withdrawn on Day 7 because of worsening motor function and excessive sedation. Subject 5 was hospitalized for delirium, dehydration, and a urinary tract infection after being found unresponsive on the floor of her home. She had not taken olanzapine for at least 24 hours. Subject 1 completed the trial but discontinued olanzapine approximately 2 months later because of worsening motor function. The study was terminated because of these events and published reports¹³ of olanzapine use in PD patients raising safety concerns.

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TABLE 1. Demographic features and effects of olanzapine on secondary outcome measures

Medication Effects
The UPDRS Activities of Daily Living subscore worsened (P<0.05) from baseline to the final observation (Figure 1 and Table 1). Caregivers reported initial improvements in nocturnal sleep and psychotic symptom intensity, but there were no statistically significant differences in hours of sleep, vital signs, caregiver distress, cognition, psychiatric symptom ratings, or motor function.

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FIGURE 1. Individual effects of olanzapine on psychotic symptoms, motor function, and Activities of Daily Living scores

DISCUSSION

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Psychosis is a common and challenging complication of PD. Pharmacotherapy is especially difficult because most neuroleptic medications aggravate parkinsonism.³ Atypical antipsychotics such as olanzapine have a lower risk of extrapyramidal side effects and may be useful in patients with PD. However, this small open-label trial was associated with functional decline, suggesting that olanzapine has limited utility for the treatment of psychosis in patients with PD and mild to moderately severe dementia.

Two earlier open-label studies suggest olanzapine is safe and effective for psychosis in PD patients, but other studies describe poor tolerance. Dosage titration schedules and patient selection might explain the different outcomes. An initial study¹⁴ included only patients without dementia and a starting dose of 1.0 mg, which is not available commercially and may have limited motor side effects. The final dose ranged from 2 to 15 mg (mean±SD=6.5±3.9 mg) and the study allowed for increases in antiparkinsonian medications after 50 days. A subsequent study¹⁵ also reported a favorable response to an 8-week trial of olanzapine starting at 5 mg in PD patients with and without dementia. The patients with dementia were more likely to withdraw from the trial, primarily because of sedation. Other anecdotal, retrospective, and prospective studies show unacceptable motor side effects with olanzapine.^{13,16,17–19} In the only controlled trial, olanzapine (mean±SD peak dose=11.4±3.5 mg/day) caused significant worsening of parkinsonism, particularly gait and bradykinesia, relative to clozapine (mean peak dose=25.8±13.5 mg/day).²⁰

Subjects in our study were terminated from the trial because of worsening parkinsonism or medical complications. Although the effect of olanzapine on motor signs was not significant, the sample size is small and fluctuating motor signs in patients with PD (as shown in Figure 1) further confound their assessment.²¹ Functional abilities, however, declined significantly. This corresponded to greater motor impairment in most cases, but incipient medical conditions may also have contributed. For most patients, enhanced parkinsonian effects occurred within the first 2 weeks, but the onset of medication intolerance varied. A possible explanation for individual differences in extrapyramidal side effects is that disease stage or dose of antiparkinsonian medications influence the amount of striatal synaptic dopamine available to compete with olanzapine for the D₂ receptor. Although it is a weak D₂ antagonist, olanzapine binds relatively tightly to the D₂ receptor and is less likely to be rapidly displaced by dopamine, especially in the setting of reduced dopamine levels.²² In contrast, some other atypical antipsychotics with higher dissociation constants (e.g., clozapine or quetiapine) are more loosely bound to the D₂ receptor and are readily displaced by dopamine, thereby reducing the risk of extrapyramidal signs.

The clinicopathological correlates of dementia and psychosis in PD are poorly understood, but extranigral pathology is presumed.²³ Olanzapine antagonism at other receptors potentially contributes to nonmotor side effects, including sedation, delirium, and orthostasis, and patients with dementia tend to be more vulnerable to these side effects. However, olanzapine did not have adverse cognitive effects in our series, as Mini-Mental State Exam scores were generally stable. Recent studies show that olanzapine has procholinergic properties, mediated via 5-HT-6 receptor activity, that potentially offset any adverse anticholinergic effects.^24,25

Most atypical antipsychotic medications (olanzapine, risperidone, quetiapine, and clozapine) have been used with variable success for PD-related psychosis.²⁶ The results of this small open-label trial, despite its shortcomings, lead us to recommend that olanzapine and other atypical neuroleptics should be used with caution in PD patients with psychosis and dementia because of their potential to aggravate motor deficits and confusion, which already contribute to functional impairment and caregiver burden.

ACKNOWLEDGMENTS

 
The authors thank Lisette Bunting, R.N., M.Sc.N. for study coordination. This study was supported by Eli Lilly, Inc, the Morris K. Udall Parkinson' s Disease Research Center of Excellence at Johns Hopkins (NIH P50-NS-58377), and the General Clinical Research Center at Johns Hopkins University School of Medicine (National Center for Research Resources/NIH M01-RR00052).

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